Greater male than female variability in regional brain structure … · 2020. 2. 17. · 4 2 Leiden...

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Greatermalethanfemalevariabilityinregionalbrainstructure

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LaraMWierenga,PhD1,2,GaelleEDoucet,PhD3,DanaiDima,PhD4,5,IngridAgartz,PhD,MD

6,7,8,MojiAghajani,PhD9,10,TheophilusNAkudjedu,PhD11,12,AntonAlbajes-Eizagirre,MSc13,14,15,

DagAlnæs,PhD6,16,KathrynIAlpert,MSc17,OleAAndreassen,PhD,MD6,16,AlanAnticevic,PhD18,

PhilipAsherson,PhD,MRCPsych19,TobiasBanaschewski,PhD,MD20,NuriaBargallo,PhD,MD21,22,

SarahBaumeister,PhD20,RamonaBaur-Streubel,PhD23,AlessandroBertolino,PhD,MD24,Aurora

Bonvino,PhD25,DorretIBoomsma,PhD26,StefanBorgwardt,MD27,28,JosianeBourque,PhD29,30,

AnoukdenBraber,PhD26,31,DanielBrandeis,PhD20,32,33,34,AlanBreier,MD35,HenryBrodaty,MD,

DSC36,37,RachelMBrouwer,PhD38,JanKBuitelaar,PhD,MD39,40,GeraldoFBusatto,PhD,MD41,

VinceDCalhoun,PhD42,ErickJCanales-Rodríguez,PhD13,14,DaraMCannon,PhD11,XavierCaseras,

PhD43,FranciscoXCastellanos,MD44,45,TiffanyMChaim-Avancini,PhD,MD41,ChristopherRK

Ching,PhD46,VincentPClark,PhD47,48,PatriciaJConrod,PhD30,49,AnnetteConzelmann,PhD50,51,

FabriceCrivello,PhD52,ChristopherGDavey,PhD,MD53,54,ErinWDickie,PhD55,56,StefanEhrlich,

PhD,MD57,Dennisvan'tEnt,PhD26,SimonEFisher,DPhil58,59,Jean-PaulFouche,PhD60,Barbara

Franke,PhD59,61,62,PaolaFuentes-Claramonte,PhD13,14,EcoJCdeGeus,PhD26,AnnabellaDi

Giorgio,PhD,MD,MSc63,DavidCGlahn,PhD64,65,IanHGotlib,PhD66,HansJGrabe,MD67,68,Oliver

Gruber,MD69,PatriciaGruner,PhD18,RaquelEGur,PhD,MD29,70,RubenCGur,PhD29,TirilP

Gurholt,PhD,MSc6,16,LieuwedeHaan,Prof.Dr.71,BeatheHaatveit,PhD6,16,BenJHarrison,PhD72,

CatharinaAHartman,PhD73,SeanNHatton,PhD74,75,DirkJHeslenfeld,PhD76,OdileAvanden

Heuvel,PhD,MD9,77,IanBHickie,MD74,PieterJHoekstra,PhD,MD78,SarahHohmann,MD20,

AvramJHolmes,PhD18,79,80,MartineHoogman,PhD59,61,NorbertHosten,MD81,FleurMHowells,

PhD82,83,HillekeEHulshoffPol,PhD38,ChaimHuyser,PhD,MD84,85,NedaJahanshad,PhD46,

AnthonyCJames,MD86,87,JiyangJiang,PhD36,ErikGJönsson,PhD,MD6,8,JohnAJoska,PhD,MD83,

AndrewJKalnin,MD88,KarolinskaSchizophreniaProject(KaSP)Consortium89,MariekeKlein,PhD

38,59,61,LauraKoenders,PhD71,KnutKKolskår,Msc16,90,91,BerndKrämer,PhD69,JonnaKuntsi,PhD

19,JimLagopoulos,PhD92,93,LuisaLazaro,PhD,MD14,94,95,96,IrinaSLebedeva,PhD97,PhilHLee,




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PhD98,99,ChristineLochner,PhD100,MariseWJMachielsen,PhD,MD101,SophieMaingault,PhD102,

NicholasGMartin,PhD103,IgnacioMartínez-Zalacaín,MSc104,105,DavidMataix-Cols,PhD8,Bernard

Mazoyer,PhD,MD106,107,BrennaCMcDonald,PsyD108,ColmMcDonald,PhD,MD11,AndrewM

McIntosh,MD109,KatieLMcMahon,PhD110,111,GenevieveMcPhilemy,PhD11,DennisvanderMeer,

PhD6,16,112,JoséMMenchón,PhD,MD14,104,105,JillyNaaijen,PhD39,LarsNyberg,PhD113,114,Jaap

Oosterlaan,PhD115,116,YannisPaloyelis,PhD5,PaulPauli,PhD117,118,GiulioPergola,PhD24,119,Edith

Pomarol-Clotet,PhD,MD13,14,MariaJPortella,PhD14,120,JoaquimRadua,PhD,MD8,13,14,15,121,

AndreasReif,MD122,GenevièveRichard,PhD6,16,90,91,JoshuaLRoffman,MD123,PedroGPRosa,MD

41,MatthewDSacchet,PhD124,PerminderSSachdev,PhD,MD36,125,RaymondSalvador,PhD13,14,

SalvadorSarró,PhD,MD13,14,TheodoreDSatterthwaite,MD126,AndrewJSaykin,PhD108,127,

MauricioHSerpa,PhD,MD41,KangSim,MD128,129,AndrewSimmons,PhD130,JordanWSmoller,

MD,ScD98,131,IrisESommer,PhD,MD132,CarlesSoriano-Mas,PhD14,104,133,DanJStein,PhD,MD134,

LachlanTStrike,PhD135,PhilipRSzeszko,PhD136,137,HenkSTemmingh,PhD83,SophiaI

Thomopoulos,BA46,AlexanderSTomyshev,MSc97,JulianNTrollor,MD36,AnneUhlmann,PhD

83,138,IlyaMVeer,PhD139,DickJVeltman,PhD,MD140,AristotleVoineskos,PhD,MD55,Henry

Völzke,MD141,142,143,HenrikWalter,PhD,MD139,LeiWang,PhD17,YangWang,PhD,MD144,Bernd

Weber,MD145,WeiWen,PhD36,JohnDWest,MSc108,LarsTWestlye,PhD6,16,90,HeatherCWhalley,

PhD109,146,StevenCRWilliams,PhD147,KatharinaWittfeld,PhD67,68,DanielHWolf,MD,PhD29,

MargaretJWright,PhD135,148,YuliyaNYoncheva,PhD149,MarcusVZanetti,PhD,MD41,150,GeorgC

Ziegler,MD151,GreigIdeZubicaray,PhD111,PaulMThompson,PhD46,EvelineACrone,PhD1,2,

SophiaFrangou,PhD,MD3,152,ChristianKTamnes,PhD6,7,153

Affiliations

1LeidenUniversity,Leiden,theNetherlands




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2LeidenInstituteforBrainandCognition,Leiden,theNetherlands

3DepartmentofPsychiatry,IcahnSchoolofMedicineatMountSinai,NewYork,USA

4DepartmentofPsychology,SchoolofArtsandSocialSciences,City,UniversityofLondon,London,

UK

5DepartmentofNeuroimaging,InstituteofPsychiatry,PsychologyandNeuroscience,King'sCollege

London,London,UK

6NorwegianCentreforMentalDisordersResearch(NORMENT),DivisionofMentalHealthand

Addiction,InstituteofClinicalMedicine,UniversityofOslo,Oslo,Norway

7DepartmentofPsychiatricResearch,DiakonhjemmetHospital,Oslo,Norway

8CentreforPsychiatryResearch,DepartmentofClinicalNeuroscience,KarolinskaInstitutet,&

StockholmHealthCareServices,StockholmCountyCouncil,Stockholm,Sweden

9DepartmentofPsychiatry,AmsterdamNeuroscience,AmsterdamUMC,VrijeUniversiteit,

Amsterdam,theNetherlands

10GGZinGeest,DepartmentofResearch&Innovation,Amsterdam,TheNetherlands

11CentreforNeuroimaging&CognitiveGenomics(NICOG),ClinicalNeuroimagingLaboratory,

NCBESGalwayNeuroscienceCentre,CollegeofMedicineNursingandHealthSciences,National

UniversityofIrelandGalway,Galway,Ireland

12InstituteofMedicalImaging&Visualisation,FacultyofHealth&SocialSciences,Bournemouth

University,Bournemouth,UK

13FIDMAGGermanesHospitalàriesResearchFoundation,Barcelona,Spain

14CentrodeInvestigaciónBiomédicaenReddeSaludMental(CIBERSAM),Madrid,Spain

15Institutd'InvestigacionsBiomèdiquesAugustPiiSunyer(IDIBAPS),Barcelona,Spain

16NorwegianCentreforMentalDisordersResearch(NORMENT),DivisionofMentalHealthand

Addiction,OsloUniversityHospital,Oslo,Norway




5

17DepartmentofPsychiatryandBehavioralSciences,NorthwesternUniversityFeinbergSchoolof

Medicine,Chicago,USA

18DepartmentofPsychiatry,YaleUniversity,NewHaven,USA

19Social,GeneticandDevelopmentalPsychiatryCentre,InstituteofPsychiatry,Psychologyand

Neuroscience,King'sCollegeLondon,London,UK

20DepartmentofChildandAdolescentPsychiatryandPsychotherapy,CentralInstituteofMental

Health,UniversityofHeidelberg,MedicalFacultyMannheim,Mannheim,Germany

21ImagingDiagnosticCenter,HospitalClínic,Barcelona,Spain

22MagneticResonanceImageCoreFacility,IDIBAPS,Barcelona,Spain

23DepartmentforClinicalPsychology,WürzburgUniversity,Margetshöchheim,Germany

24DepartmentofBasicMedicalScience,NeuroscienceandSenseOrgans,UniversityofBariAldo

Moro,Bari,Italy

25UniversityofBariAldoMoro,Bari,Italy

26DepartmentofBiologicalPsychology,VUUniversityAmsterdam,Amsterdam,theNetherlands

27DepartmentofPsychiatry,UniversityofBasel,Basel,Switzerland

28DepartmentofPsychiatry,UniversityofLübeck,Lübeck,Germany

29DepartmentofPsychiatry,UniversityofPennsylvania,Philadelphia,USA

30CHUSainte-JustineResearchCenter,Montreal,Quebec,Canada

31AlzheimerCenter,AmsterdamUMC,LocationVUMC,Amsterdam,theNetherlands

32DepartmentofChildandAdolescentPsychiatryandPsychotherapy,PsychiatricHospital,

UniversityofZurich,Zurich,Switzerland

33ZurichCenterforIntegrativeHumanPhysiology,UniversityofZurich,Zurich,Switzerland

34NeuroscienceCentreZurich,UniversityandETHZurich,Zurich,Switzerland

35DepartmentofPsychiatry,IndianaUniversitySchoolofMedicine,Indianapolis,USA




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36CentreforHealthyBrainAgeing,SchoolofPsychiatry,UniversityofNewSouthWales,Sydney,

Australia

37DementiaCentreforResearchCollaboration,SchoolofPsychiatry,UniversityofNewSouth

Wales,Sydney,Australia

38DepartmentofPsychiatry,UniversityMedicalCenterUtrechtBrainCenter,UtrechtUniversity,

Utrecht,theNetherlands

39DepartmentofCognitiveNeuroscience,RadboudUniversityMedicalCentre,Nijmegen,the

Netherlands

40KarakterChildandAdolescentPsychiatryUniversityCentre,Nijmegen,theNetherlands

41LaboratoryofPsychiatricNeuroimaging(LIM-21),DepartamentoeInstitutodePsiquiatria,

HospitaldasClinicasHCFMUSP,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,

Brazil

42Tri-institutionalCenterforTranslationalResearchinNeuroimagingandDataScience(TReNDS),

GeorgiaState,GeorgiaTech,Emory,Atlanta,USA

43MRCCentreforNeuropsychiatricGeneticsandGenomics,CardiffUniversity,Cardiff,UK

44DepartmentofChildandAdolescentPsychiatry,NYUGrossmanSchoolofMedicine,NewYork,

USA

45NathanKlineInstituteforPsychiatricResearch,Orangeburg,NY,USA

46ImagingGeneticsCenter,MarkandMaryStevensNeuroimagingandInformaticsInstitute,Keck

SchoolofMedicine,UniversityofSouthernCalifornia,MarinadelRey,USA

47PsychologyClinicalNeuroscienceCenter,DepartmentofPsychology,UniversityofNewMexico,

Albuquerque,NM,USA

48MindResearchNetwork,Albuquerque,NM,USA

49DepartmentofPsychiatry,UniversityofMontreal,Montreal,Canada




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50DepartmentofChildandAdolescentPsychiatry,PsychosomaticsandPsychotherapy,University

ofTübingen,Tübingen,Germany

51PFH–PrivateUniversityofAppliedSciences,DepartmentofPsychology(ClinicalPsychologyII),

Göttingen,Germany

52Grouped’ImagerieNeurofonctionnelle,InstitutdesMaladiesNeurodégénératives,Bordeaux,

France

53CentreforYouthMentalHealth,UniversityofMelbourne,Parkville,Australia

54Orygen,Parkville,Victoria,Australia

55CampbellFamilyMentalHealthInstitute,CentreforAddictionandMentalHealth,Departmentof

Psychiatry,UniversityofToronto,Toronto,Canada

56DepartmentofPsychiatry,UniversityofToronto,Toronto,Ontario,Canada

57DivisionofPsychological&SocialMedicineandDevelopmentalNeurosciences;Technische

UniversitätDresden,FacultyofMedicine,UniversityHospitalC.G.Carus,TU-Dresden,Dresden,

Germany

58LanguageandGeneticsDepartment,MaxPlanckInstituteforPsycholinguistics,Nijmegen,the

Netherlands

59DondersInstituteforBrain,CognitionandBehaviour,RadboudUniversity,Nijmegen,the

Netherlands

60DepartmentofPsychiatryandNeuroscienceInstitute,UniversityofCapeTown,CapeTown,

WesternCape,SouthAfrica

61DepartmentofHumanGenetics,RadboudUniversityMedicalCenter,Nijmegen,theNetherlands

62DepartmentofPsychiatry,RadboudUniversityMedicalCenter,Nijmegen,theNetherlands

63IRCCSCasaSollievodellaSofferenza,SanGiovanniRotondo,Italy

64TommyFussCenterforNeuropsychiatricDiseaseResearch,DepartmentofPsychiatry,Boston

Children'sHospitalandHarvardMedicalSchool,Boston,USA




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65OlinCenterforNeuropsychiatricResearch,InstituteofLiving,HartfordHospital,Hartford,CT,

USA

66DepartmentofPsychology,StanfordUniversity,Stanford,USA

67DepartmentofPsychiatryandPsychotherapy,UniversityMedicineGreifswald,Greifswald,

Germany

68GermanCenterforNeurodegenerativeDiseases(DZNE),SiteRostock/Greifswald,Greifswald,

Germany

69SectionforExperimentalPsychopathologyandNeuroimaging,DepartmentofGeneralPsychiatry,

HeidelbergUniversityHospital,Heidelberg,Germany

70LifespanBrainInstitute,Children'sHospitalofPhiladelphia,Philadelphia,Pennsylvania,USA

71DepartmentofEarlyPsychosis,AmsterdamUMC,Amsterdam,theNetherlands

72MelbourneNeuropsychiatryCentre,DepartmentofPsychiatry,TheUniversityofMelbourne&

MelbourneHealth,Melbourne,Australia

73InterdisciplinaryCenterPsychopathologyandEmotionregulation,UniversityofGroningen,

UniversityMedicalCenterGroningen,Groningen,theNetherlands

74BrainandMindCentre,UniversityofSydney,Sydney,Australia

75DepartmentofNeurosciences,UniversityofCaliforniaSanDiego,LaJolla,CA,USA

76DepartmentsofExperimentalandClinicalPsychology,VrijeUniversiteitAmsterdam,Amsterdam,

theNetherlands

77DepartmentofAnatomy&Neurosciences,AmsterdamNeuroscience,AmsterdamUMC,Vrije

UniversiteitAmsterdam,Amsterdam,theNetherlands

78DepartmentofPsychiatry,UniversityofGroningen,UniversityMedicalCenterGroningen,

Groningen,theNetherlands

79DepartmentofPsychology,YaleUniversity,NewHaven,USA

80DepartmentofPsychiatry,MassachusettsGeneralHospital,Boston,MA,USA




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81InstituteofDiagnosticRadiologyandNeuroradiology,UniversityMedicineGreifswald,

Greifswald,Germany

82NeuroscienceInstitute,UniversityofCapeTown,CapeTown,WesternCape,SouthAfrica

83DepartmentofPsychiatryandMentalHealth,UniversityofCapeTown,CapeTown,Western

Cape,SouthAfrica

84DeBascule,Academiccenterchildandadolescentpsychiatry,Duivendrecht,theNetherlands

85AmsterdamUMCdepartmentofchildandadolescentpsychiatry,Amsterdam,theNetherlands

86DepartmentofPsychiatry,WarnefordHospital,Oxford,UK

87HighfieldUnit,WarnefordHospital,Oxford,UK

88DepartmentofRadiology,TheOhioStateUniversityCollegeofMedicine,Columbus,Ohio,USA

89MembersofKarolinskaSchizophreniaProject(KaSP)Consortiumarelistedattheendofthe

manuscriptascollaborators

90DepartmentofPsychology,UniversityofOslo,Oslo,Norway

91SunnaasRehabilitationHospitalHT,Nesodden,Norway

92SunshineCoastMindandNeuroscienceThompsonInstitute,Birtinya,Australia

93UniversityoftheSunshineCoast,Australia

94DepartmentofChildandAdolescentPsychiatryandPsychology,HospitalClínic,Barcelona,Spain,

Barcelona,Spain

95AugustPiiSunyerBiomedicalResearchInstitut(IDIBAPS),Barcelona,Spain

96DepartmentofMedicine,UniversityofBarcelona,Barcelona,Spain

97LaboratoryofNeuroimagingandMultimodalAnalysis,MentalHealthResearchCenter,Moscow,

Russia

98DepartmentofPsychiatry,MassachusettsGeneralHospital,Boston,USA

99DepartmentofPsychiatry,HarvardMedicalSchool,Boston,MA,USA




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100SAMRCUnitonRiskandResilienceinMentalDisorders,DepartmentofPsychiatry,Stellenbosch

University,CapeTown,WesternCape,SouthAfrica

101DepartmentofPsychiatry,AcademicMedicalCenter,Amsterdam,theNetherlands

102Institutdesmaladiesneurodégénératives,UniversitédeBordeaux,Bordeaux,France

103GeneticEpidemiology,QIMRBerghoferMedicalResearchInstitute,Brisbane,Australia

104DepartmentofPsychiatry,BellvitgeUniversityHospital,BellvitgeBiomedicalResearchInstitute-

IDIBELL,Barcelona,Spain

105DepartmentofClinicalSciences,UniversityofBarcelona,Barcelona,Spain

106UniversityofBordeaux,Bordeaux,France

107BordeauxUniversityHospital,Bordeaux,France

108DepartmentofRadiologyandImagingSciences,IndianaUniversitySchoolofMedicine,

Indianapolis,USA

109DivisionofPsychiatry,UniversityofEdinburgh,Edinburgh,UK

110HerstonImagingResearchFacilityandSchoolofClinicalSciences,QueenslandUniversityof

Technology(QUT),Brisbane,Australia

111FacultyofHealth,InstituteofHealthandBiomedicalInnovation,QueenslandUniversityof

Technology(QUT),Brisbane,Australia

112SchoolofMentalHealthandNeuroscience,FacultyofHealth,MedicineandLifeSciences,

MaastrichtUniversity,Maastricht,theNetherlands

113DepartmentofRadiationSciences,UmeåUniversity,Umeå,Sweden

114DepartmentofIntegrativeMedicalBiology,UmeåUniversity,Umeå,Sweden

115EmmaChildren'sHospital,AmsterdamUMCUniversityofAmsterdamandVrijeUniversiteit

Amsterdam,EmmaNeuroscienceGroup,DepartmentofPediatrics,AmsterdamReproduction&

Development,Amsterdam,theNetherlands

116ClinicalNeuropsychologySection,VrijeUniversiteitAmsterdam,Amsterdam,theNetherlands




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117DepartmentofPsychology,UniversityofWürzburg,Würzburg,Germany

118CentreofMentalHealth,MedicalFaculty,UniversityofWürzburg,Würzburg,Germany

119LieberInstituteforBrainDevelopment,JohnsHopkinsMedicalCampus,Baltimore,MD,USA

120DepartmentofPsychiatry,Institutd'InvestigacióBiomèdicaSantPau,Barcelona,Spain

121EarlyPsychosis:InterventionsandClinical-detection(EPIC)lab,DepartmentofPsychosis

Studies,InstituteofPsychiatry,PsychologyandNeuroscience,King'sCollegeLondon,London,UK

122DepartmentofPsychiatry,PsychosomaticMedicineandPsychotherapy,UniversityHospital

Frankfurt,FrankfurtAmMain,Germany

123DepartmentofPsychiatry,MassachusettsGeneralHospitalandHarvardMedicalSchool,

Charlestown,USA

124CenterforDepression,Anxiety,andStressResearch,McLeanHospital,HarvardMedicalSchool,

Belmont,USA

125NeuropsychiatricInstitute,ThePrinceofWalesHospital,Randwick,NSW,Australia

126DepartmentofPsychiatry,UniversityofPennsylvania,Philadelphia,USA

127IndianaAlzheimerDiseaseCenter,Indianapolis,Indiana,USA

128WestRegion,InstituteofMentalHealth,Singapore,Singapore

129YongLooLinSchoolofMedicine,NationalUniversityofSingapore,Singapore

130DepartmentofNeuroimaging,InstituteofPsychiatry,PsychologyandNeurology,King'sCollege

London,London,UK

131PsychiatricandNeurodevelopmentalGeneticsUnit,CenterforGenomicMedicine,Massachusetts

GeneralHospital,Boston,Massachusetts,USA

132DepartmentofBiomedicalSciencesofCellsandSystems,RijksuniversiteitGroningen,University

MedicalCenterGroningen,Groningen,theNetherlands

133DepartmentofPsychobiologyandMethodologyinHealthSciences,UniversitatAutònomade

Barcelona,Barcelona,Spain




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134SAMRCUnitonRisk&ResilienceinMentalDisorders,DeptofPsychiatry&Neuroscience

Institute,UniversityofCapeTown,CapeTown,WesternCape,SouthAfrica

135QueenslandBrainInstitute,UniversityofQueensland,Brisbane,Australia

136DepartmentofPsychiatry,IcahnSchoolofMedicineatMountSinai,NewYork,USA

137MentalIllnessResearch,EducationandClinicalCenter(MIRECC),JamesJ.PetersVAMedical

Center,Bronx,NewYork,USA

138DepartmentofChildandAdolescentPsychiatryandPsychotherapy,FacultyofMedicineCarl

GustavCarusofTUDresden,Dresden,Germany

139DepartmentofPsychiatryandPsychotherapyCCM,Charité-UniversitätsmedizinBerlin,

corporatememberofFreieUniversitätBerlin,Humboldt-UniversitätzuBerlin,andBerlinInstitute

ofHealth,Berlin,Germany

140DepartmentofPsychiatry&AmsterdamNeuroscience,AmsterdamUMC,locationVUMC,

Amsterdam,theNetherlands

141InstituteforCommunityMedicine,UniversityMedicineGreifswald,Greifswald,Germany

142DZHK(GermanCentreforCardiovascularResearch),partnersiteGreifswald,Greifswald,

Germany

143DZD(GermanCenterforDiabetesResearch),partnersiteGreifswald,Greifswald,Germany

144DepartmentofRadiology,MedicalCollegeofWisconsin,Milwaukee,USA

145InstituteforExperimentalEpileptologyandCognitionResearch,UniversityHospitalBonn,Bonn,

Germany

146DivisionofPsychiatry,RoyalEdinburghHospital,Edinburgh,UK

147DepartmentofNeuroimaging,King'sCollegeLondon,London,UK

148CentreforAdvancedImaging,UniversityofQueensland,Brisbane,Queensland,Australia

149DepartmentofChildandAdolescentPsychiatry,NYUChildStudyCenter,HassenfeldChildren’s

HospitalatNYULangone,NewYork,USA




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150InstitutodeEnsinoePesquisa,HospitalSírio-Libanês,SãoPaulo,Brazil

151DivisionofMolecularPsychiatry,CenterofMentalHealth,UniversityofWürzburg,Würzburg,

Würzburg,Germany

152CentreforBrainHealth,UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada

153PROMENTAResearchCenter,DepartmentofPsychology,UniversityofOslo,Oslo,Norway

Correspondingauthor:LaraM.Wierenga

E-mail:[email protected]




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Numberoffiguresandtables:6figures,3tables,Supplementalfigures3,Supplementaltables3

Numberofwordsabstract:1619words

NumberofwordsIntroduction:760words

NumberofwordsMethods:1153words

NumberofwordsResults:978words

NumberofwordsDiscussionandConclusion:1375words

Numberofreferences:62




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AbstractFormanytraits,malesshowgreatervariabilitythanfemales,withpossibleimplicationsfor

understandingsexdifferencesinhealthanddisease.Here,theENIGMA(EnhancingNeuroImaging

GeneticsthroughMeta-Analysis)Consortiumpresentsthelargest-evermega-analysisofsex

differencesinvariabilityofbrainstructure,basedoninternationaldataspanningninedecadesof

life.Subcorticalvolumes,corticalsurfaceareaandcorticalthicknesswereassessedinMRIdataof

16,683healthyindividuals1-90yearsold(47%females).Weobservedsignificantpatternsof

greatermalethanfemalebetween-subjectvarianceforallsubcorticalvolumetricmeasures,all

corticalsurfaceareameasures,and60%ofcorticalthicknessmeasures.Thispatternwasstable

acrossthelifespanfor50%ofthesubcorticalstructures,70%oftheregionalareameasures,and

nearlyallregionsforthickness.Ourfindingsthatthesesexdifferencesarepresentinchildhood

implicateearlylifegeneticorgene-environmentinteractionmechanisms.Thefindingshighlightthe

importanceofindividualdifferenceswithinthesexes,thatmayunderpinsex-specificvulnerability

todisorders.




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IntroductionForadiversesetofhumantraitsandbehaviors,malesareoftenreportedtoshowgreater

variabilitythanfemales(Hyde2014).Thissexdifferencehasbeennotedforaspectsofpersonality

(Borkenau,McCrae,andTerracciano2013),cognitiveabilities(ArdenandPlomin2006;Johnson,

Carothers,andDeary2008;Roalfetal.2014),andschoolachievement(BayeandMonseur2016).A

fundamentalquestionistowhatdegreethesesexdifferencesarerelatedtogeneticmechanismsor

socialfactors,ortheirinteractions.Lehreetal.(2009)foundcompellingevidenceforanearly

geneticorinuterocontribution,reportinggreatermalevariabilityinanthropometrictraits(e.g.

bodyweightandheight,bloodparameters)alreadydetectableatbirth.Recentstudiessuggest

greatermalevariabilityalsoinbrainstructureanditsdevelopment(Fordeetal.2019;Ritchieetal.

2018;Wierengaetal.2017;2019),butstudieswithlargersamplesthatcoverbothearlychildhood

andoldagearecriticallyneeded.Specifically,wedonotknowwhensexdifferencesinvariabilityin

brainstructureemergeandwhethertheychangewithdevelopmentandthroughoutlife.Yet,data

onthiscouldinformusontheoriginsandfactorsthatinfluencethisphenomenon.Forthisreason,

wesetouttoanalyzemagneticresonanceimaging(MRI)datafromalargesampleofindividuals

acrossaverywideagerange(n=16,683,age1-90)torobustlycharacterizesexdifferencesin

variabilityofbrainstructureandtesthowthesedifferencesinteractwithage.

Manypriorstudiesreportsexdifferencesinbrainstructure,butthespecificity,regionalpattern

andfunctionalrelevanceofsucheffectsarenotclear(Hertingetal.2018;KoolschijnandCrone

2013;Marwha,Halari,andEliot2017;Ruigroketal.2014;Tanetal.2016).Onereasoncouldbe

thatmoststudieshaveexaminedmeandifferencesbetweenthesexes,whilesexdifferencesin

variabilityremainunderstudied(DelGiudiceetal.2016;Joeletal.2015).Asmeanandvariance

measuretwodifferentaspectsofthedistribution(centerandspread),knowledgeonvariance

effectsmayprovideimportantinsightsintosexdifferencesinthebrain.Recentstudiesobserved

greatermalevarianceforsubcorticalvolumesandforcorticalsurfaceareatoalargerextentthan




17

forcorticalthickness(Ritchieetal.2018;Wierengaetal.2017;2019).However,furtherstudiesare

neededtoexploreregionalpatternsofvariancedifferences,and,critically,totesthowsex

differencesinvariabilityinthebrainunfoldacrossthelifespan.

Animportantquestionpertainstothemechanismsinvolvedinsexdifferencesinvariability.It

ishypothesizedthatthelackoftwoparentalX-chromosomalcopiesinhumanmalesmaydirectly

relatetogreatervariabilityandvulnerabilitytodevelopmentaldisordersinmalescomparedto

females(Arnold2012).AllcellsinmalesexpressanX-linkedvariant,whilefemalebraintissues

showtwovariants.Infemales,oneoftheX-chromosomesisrandomlysilenced,assuchneighboring

cellsmayhavedifferentXrelatedgeneticexpression(Wuetal.2014).Consequently,onecould

expectthatinadditiontogreatervariabilityacrossthepopulation,interregionalanatomical

correlationsmaybestrongerinmalerelativetofemalebrains.Thiswasindeedobservedfora

numberofregionalbrainvolumesinchildrenandadolescents,showinggreaterwithin-subject

homogeneityacrossregionsinmalesthanfemales(Wierengaetal.2017).Theseresultsremainto

bereplicatedinlargersamplesastheymayprovidecluesaboutmechanismsandriskfactorsin

neurodevelopmentaldisorders(e.g.attention-deficit/hyperactivitydisorderandautismspectrum

disorder)thatshowsexdifferencesinprevalence(BaoandSwaab2010),ageofonset,heritability

rates(Costelloetal.2003),orseverityofsymptomsandcourse(Goldstein,Seidman,andO'brien

2002).

Inthepresentstudy,weperformedmega-analysesondatafromtheENIGMA(Enhancing

NeuroImagingGeneticsthroughMeta-Analysis)Lifespanworkinggroup(Dimaetal.,2020;Frangou

etal.,2020;JahanshadandThompson2016).Amega-analysisallowsforanalysesofdatafrom

multiplesiteswithasinglestatisticalmodelthatfitsalldataandsimultaneouslyaccountingforthe

effectofsite.Successfullypoolinglifespandatawasrecentlyshowninastudycombining18

datasetstoderiveagetrendsofbrainstructure(Pomponioetal.2020).Thiscontrastswithmeta-




18

analysiswheresummarystatisticsarecombinedandweightedfromdatathatisanalyzedateach

site(vanErpetal.2019).MRIdatafromalargesample(n=16,683)ofparticipantsaged1to90

yearswasincluded.Weinvestigatedsubcorticalvolumesandregionalcorticalsurfaceareaand

thickness.Ourfirstaimwastoreplicatepreviousfindingsofgreatermalevariabilityinbrain

structureinasubstantiallylargersample.Basedonpriorstudies(Fordeetal.2019;Ritchieetal.

2018;Wierengaetal.2017;2019)andreportsofsomewhatgreatergeneticeffectonsurfacearea

thanthickness(Eyleretal.2011;Kremenetal.2013),wehypothesizedthatgreatermalevariance

wouldbemorepronouncedforsubcorticalvolumesandcorticalsurfaceareathanforcortical

thickness,andthatgreatermalevariancewouldbeobservedatbothupperandlowerendsofthe

distribution.Oursecondaimwastotestwhetherobservedsexdifferencesinvariabilityofbrain

structurearestableacrossthelifespanfrombirthuntil90yearsofage,ore.g.increasewiththe

accumulationofexperiences(Pfefferbaum,Sullivan,andCarmelli2004).Third,inlinewiththe

singleX-chromosomehypothesis,weaimedtoreplicatewhethermalesshowgreaterinterregional

anatomicalcorrelations(i.e.within-subjecthomogeneity)acrossbrainregionsthatshowgreater

malecomparedtofemalevariance(Wierengaetal.2019).

Methods

Participants

ThedatasetsanalyzedinthepresentstudywerefromtheLifespanworkinggroupwithinthe

ENIGMAConsortium(JahanshadandThompson2016).Therewere78independentsampleswith

MRIdata,intotalincluding16,683(7,966males)healthyparticipantsaged1-90yearsfromdiverse

ethnicbackgrounds(seedetaileddescriptionsatthecohortlevelinTable1).Samplesweredrawn

fromthegeneralpopulationorwerehealthycontrolsinclinicalstudies.Screeningproceduresand

theeligibilitycriteria(e.g.headtrauma,neurologicalhistory)maybefoundinSupplementalTable




19

1.Participantsineachcohortgavewritteninformedconsentatthelocalsites.Furthermore,ateach

sitelocalresearchethicscommitteesorInstitutionalReviewBoardsgaveapprovalforthedata

collection,andalllocalinstitutionalreviewboardspermittedtheuseofextractedmeasuresofthe

completelyanonymizeddatathatwereusedinthepresentstudy.

ImagingDataAcquisitionandProcessing

Fordefinitionofallbrainmeasures,whole-brainT1-weightedanatomicalscanwereincluded.

Detailedinformationonscannermodelandimageacquisitionparametersforeachsitecanbefound

inSupplementalTable1.T1weightedscanswereprocessedatthecohortlevel,wheresubcortical

segmentationandcorticalparcellationwereperformedbyrunningtheT1-weightedimagesin

FreeSurferusingversions4.1,5.1,5.3or6.0(seeSupplementalTable1forspecificationspersite).

Thissoftwaresuiteiswellvalidatedandwidelyused,anddocumentedandfreelyavailableonline

(surfer.nmr.mgh.harvard.edu).Thetechnicaldetailsoftheautomatedreconstructionschemeare

describedelsewhere(Dale,Fischl,andSereno1999;Fischletal.1999;2002).Theoutcome

variablesincludedvolumesofsevensubcorticalstructures:accumbens,caudate,pallidum,

putamen,amygdala,hippocampus,andthalamus(Fischletal.2002),andcorticalsurfaceareaand

thicknessmeasures(Daleetal.1999;Fischletal.1999)of68regionsofthecerebralcortex

(Desikan-Killianyatlas)(Desikanetal.2006).Qualitycontrolwasalsoimplementedatthecohort

levelfollowingdetailedprotocols(http://enigma.ini.usc.edu/protocols/imaging-protocols).The

statisticalanalysesincluded13,696participantsforsubcorticalvolumes,11,338forsurfacearea

measures,and12,533participantsforcorticalthicknessanalysis.

StatisticalAnalysis

StatisticalanalyseswereperformedusingRStatisticalSoftware.Thecompletescriptsare

availableintheSupplementalmaterialsintheSIAppendix.Inbrief,wefirstadjustedallbrain

structurevariablesforcohort,fieldstrengthandFreeSurferversioneffects.Asagerangesdiffered




20

foreachcohortthiswasdoneintwosteps:initially,alinearmodelwasusedtoaccountforcohort

effectsandnon-linearageeffects,usingathird-degreepolynomialfunction.Next,randomforest

regressionmodelling(Breiman2001)wasusedtoadditionallyaccountforfieldstrengthand

FreeSurferversion.SeeSupplementalFigure1foradjustedvalues.ThiswasimplementedintheR

packagerandomForest,whichcanaccommodatemodelswithinteractionsandnon-lineareffects.

Meandifferences

Meansexdifferencesinbrainstructurevariablesweretestedusingt-tests(FDRcorrected,

see(BenjaminiandHochberg1995))andeffectsizeswereestimatedusingCohen’sd-value.A

negativeeffectsizeindicatesthatthemeanwashigherinfemales,andapositiveeffectsize

indicatesitwashigherinmales.Thebrainstructurevariableswereadjustedforageandcovariates

describedabove.GraphswerecreatedwithRpackageggseg(MowinckelandVIdal-Pineiro,2019).

Varianceratio

Variancedifferencesbetweenmalesandfemaleswereexamined,afteraccountingforageand

othercovariatesasdescribedabove.Fisher’svarianceratio(VR)wasestimatedbydividing

variancemeasuresformalesandfemales.VRwaslogtransformedtoaccountforVRbias(Katzman

andAlliger1992;Lehreetal.2009).Letting𝑦" denotetheobservedoutcomeforobservation

number𝑖and𝑦ˆ" itspredictedoutcome,theresidualswerethenformed:

𝑟" = 𝑦" − 𝑦ˆ"

Theresidualvariance𝑉𝑎𝑟 +,-./and𝑉𝑎𝑟 0.+,-./werecomputedseparatelyformalesand

females,andusedtoformtheteststatistic

𝑇 = 𝑉𝑎𝑟 +,-.//𝑉𝑎𝑟 0.+,-./




21

Foreachoutcome,apermutationtestofthehypothesisthatthesexspecificstandarddeviations

wereequal,wasperformed.Thiswasdonebyrandompermutationofthesexvariableamongthe

residuals.Using𝛽permutations,the𝑝-valueforthe𝑘-thoutcomemeasurewascomputedas

𝑝6 =7

89:

𝐼(𝑇8 > 𝑇)/𝐵

where𝐼(𝑇8 ≥ 𝑇)isanindicatorfunctionthatis1when𝑇8 ≥ 𝑇,and0otherwise.Thus,the𝑝-valueis

theproportionofpermutedteststatistics(𝑇8)thatweregreaterthantheobservedvalue𝑇ofthe

teststatisticabove.Here𝐵wassetto10,000.FDRcorrectedvaluesarereportedassignificant.

ShiftFunction

Toassessthenatureofthevariabilitydifferencebetweenmalesandfemales,shiftfunctions

wereestimatedforeachbrainmeasurethatshowedsignificantvariancedifferencesbetweenmales

andfemalesusingquantileregressionforests(Meinshausen2006;Rousselet,Pernet,andWilcox

2017),implementedintheRpackagequantregForest(seeWierengaetal.2017)forasimilar

approach).First,asdescribedabove,brainmeasureswereaccountedforsite,age,fieldstrengthand

FreeSurferversion.Next,quantiledistributionfunctionswereestimatedformalesandfemales

separatelyafteraligningthedistributionmeans.Let𝑞beaprobabilitybetween0and1.The

quantilefunctionspecifiesthevaluesatwhichthevolumeofabrainmeasurewillbeatorbelow

anygiven𝑞.Thequantilefunctionformalesisgivenas𝑄(𝑞|𝑚𝑎𝑙𝑒𝑠)andforfemalesas

𝑄(𝑞|𝑓𝑒𝑚𝑎𝑙𝑒𝑠).Thequantiledistancefunctionisthendefinedas:

𝐷(𝑞) = 𝑄(𝑞|𝑚𝑎𝑙𝑒𝑠) − 𝑄(𝑞|𝑓𝑒𝑚𝑎𝑙𝑒𝑠)

Abootstrapmethodwasusedtoestimatethestandarderrorofthequantiledifference

functions,whichwasusedtoformapproximate95%confidenceintervals.Ifthequantiledistance

functionisastraight-lineparalleltothexaxis,thisindicatesastabledifferencebetweenthesexes




22

acrossthedistributionandthusnodetectabledifferenceinvariability.Apositiveslopeindicates

greatermalevariance.Morespecifically,thiswouldindicatethatthemaleswiththelargestvalues

haverelativelylargervaluesthanfemaleswiththelargestvalues,andmaleswiththesmallest

valuesarerelativelysmallervaluesthanthefemaleswiththesmallestvalues.Anegativeslopeof

thequantiledistancefunctionwouldindicatelargervariabilityinfemalesatbothendsofthe

distribution.

Variancechangewithage

Tostudywhetherthesexdifferencesinvariancearestableacrosstheagerangeweusedthe

residualsofthepredictedoutcomemeasureandeachindividual𝑖:

𝑟" = |𝑦" − 𝑦ˆ"|

Theabsolutevalueof𝑟" wasthenusedinaregressionmodel.Itwasnextexploredwhether

therewasasignificant(FDRcorrected)agebysexinteractioneffectusingalinearmodel1and

quadraticmodel2:

𝑦" = 𝐴𝑔𝑒" ∗ 𝑠𝑒𝑥" + 𝑒𝑟𝑟𝑜𝑟"(𝑚𝑜𝑑𝑒𝑙1)

𝑦" = 𝐴𝑔𝑒"R ∗ 𝑠𝑒𝑥" + 𝑒𝑟𝑟𝑜𝑟"(𝑚𝑜𝑑𝑒𝑙2)

Anatomicalcorrelationanalysis

Inter-regionalanatomicalassociationswereassessedbydefiningthecorrelationbetweentwo

brainstructures,afteraccountingforageandothercovariatesasdescribedabove.Anatomical

correlationmatriceswereestimatedaspreviouslyappliedinseveralstructuralMRIstudiesfor

malesandfemalesseparately(seee.g.Baaréetal.2001;Lerchetal.2006).Next,theanatomical




23

correlationmatrixforfemaleswassubtractedfromtheanatomicalcorrelationmatrixformales,

yieldingadifferencematrix.

Thus,thePearsoncorrelationcoefficientbetweenanytworegions𝑖and𝑗wasassessedfor

malesandfemalesseparately.Thisproducedtwogroupcorrelationmatrices𝑀"V and𝐹"V where

𝑖, 𝑗, = 1,2, . . . . , 𝑁,where𝑁isthenumberofbrainregions.

Sexspecificmeansandstandarddeviationswereremovedbyperformingsexspecific

standardization.Thesignificanceofthedifferencesbetween𝑴𝒊𝒋and𝑭𝒊𝒋wasassessedby

thedifferenceintheirFisher’s𝒛-transformedvalues,and𝒑-valueswerecomputedusing

permutations.Whetherthesesignificantlydifferedbetweenthesexeswastestedusinga

Chi-squaretest.

Results

SexDifferencesinMeanandVariance

Allbrainmeasureswereadjustedforcohort,fieldstrength,FreeSurferversionand(non-linear)

age.Asabackgroundanalysis,wefirstassessedwhetherbrainstructuralmeasuresshowedmean

differencesbetweenmalesandfemalestoalignourfindingstopreviousreports(Figure1,Table

2A-C).Allsubcorticalvolumesweresignificantlylargerinmales,witheffectsizes(Cohen’sd-

values)rangingfrom0.41(leftaccumbens)to0.92(rightthalamus),andanaverageeffectsizeof

0.7.Infollow-upanalyseswithtotalbrainvolumeasanadditionalcovariatewefoundasimilar

pattern,althougheffectsizesweresmaller(SupplementalTableS2A).Alsoforcorticalsurfacearea,

allregionsshowedsignificantlylargervaluesinmalesthanfemales,witheffectsizesrangingfrom

0.42(leftcaudalanteriorcingulatearea)to0.97(leftsuperiortemporalarea),onaverage0.71.

Whentotalsurfaceareawasincludedasanadditionalcovariate,asimilarpatternwasobserved,




24

althougheffectsizesweresmaller(SupplementalTableS2B).Corticalthicknessshowedsignificant

meansexdifferencesin43(outof68)regions,ofwhich38regionsshowedlargerthicknessvalues

infemalesthanmales.Theseweremostlyfrontalandparietalregions.Thelargesteffectsize,

however,wasonly0.12(rightcaudalanteriorcingulatecortex).Whentotalaveragecortical

thicknesswasincludedasanadditionalcovariate,nineregionsshowedamaleadvantagethatwas

notobservedintherawdataanalysis,andsixofthe38regionsshowingfemaleadvantagedidnot

reachsignificance(SupplementalTableS2C).

Wethentestedforsexdifferencesinvarianceofbrainstructure,adjustedforcohort,field

strength,FreeSurferversionand(non-linear)age(Figure2,Tables2A-C).Allsubcorticalvolumes

hadsignificantlygreatervarianceinmalesthanfemales.Logtransformedvarianceratiosranged

from0.12(rightaccumbens)to0.36(rightpallidum),indicatinggreatervarianceinmalesthan

females.Similarresultswerealsoobservedwhentotalbrainvolumewastakenintoaccount

(SupplementalTableS2A).Corticalsurfaceareaalsoshowedsignificantlygreatervarianceinmales

forallregions:varianceratiosrangedfrom0.13(leftcaudalanteriorcingulatecortex)to0.36(right

parahippocampalcortex).Thispatternwasalsoobservedwhentotalsurfaceareawasincludedin

themodel(SupplementalTableS2B).Corticalthicknessshowedsignificantlygreatermalevariance

in41outof68regions,withthegreatestvarianceratiobeing0.11(leftprecentralcortex).Notably,

37ofthese41regionsdidnotshowsignificantlylargermeanthicknessvaluesinmales.When

additionallyaccountingfortotalaveragethickness,wefoundgreatermalevariancein39regions

andgreaterfemalesvariancein5regions.Alsohere,significantvarianceratioswerepresentinthe

absenceofmeansexdifferences(SupplementalTableS2C).

Next,wedirectlytestedwhethertheregionsshowinglargervarianceeffectswerealsothose

showinglargermeandifferences,bycorrelatingthevarianceratioswiththevectorofd-values

(SupplementalFigure2).Therewasasignificantassociationforsubcorticalvolumes(r(12)=0.7,




25

P-value=0.005),butnosignificantrelationforregionalcorticalsurfacearea(r(66)=0.18,P-value

=0.14),orthickness(r(66)=-0.21,P-value=0.09).

GreaterVarianceinMalesatUpperandLowerTails

Inordertocharacterisehowthedistributionsofmalesandfemalesdiffer,quantileswere

comparedusingashiftfunction(Rousseletetal.2017).Asinthepreviousmodels,brainmeasures

wereadjustedforcohort,fieldstrength,FreeSurferversionandage.Inaddition,thedistribution

meanswerealigned.Resultsshowedgreatermalevarianceatbothupperandlowertailsfor

regionsthatshowedsignificantvariancedifferencesbetweenmalesandfemales.Thetopthree

varianceratioeffectsforsubcorticalvolume,corticalsurfaceareaandcorticalthicknessareshown

inFigure3.

VarianceDifferenceBetweenSexesAcrossAge

Wenexttestedwhetherthesexdifferencesinvarianceinteractedwithage(Figure4and

supplementalFigure3).Inthissetofanalyses,brainmeasureswereadjustedforcohort,field

strength,andFreeSurferversion.For50%ofthesubcorticalvolumemeasurestherewasa

significantinteraction,specificallyforthebilateralthalami,bilateralputamen,bilateralpallidum

andthelefthippocampus(Table3A,Figure5).Corticalsurfaceareashowedsignificantinteraction

effectsin30%ofthecorticalregions(Table3C,Figure5).Inbothcases,youngerindividualstended

toshowgreatersexdifferencesinvariancethanolderindividuals.Forcorticalthickness,an

interactionwithagewasdetectedonlyintheleftinsula(Table3B,Figure5).Thisregionshowed

greatermalethanfemalevarianceintheyoungeragegroup,whereasgreaterfemalevariancewas

observedinolderindividuals.

Next,theseanalyseswererepeatedusingaquadraticagemodel(SupplementalTables3A-C).

Noneofthesubcorticalorcorticalsurfaceareameasuresshowedquadraticagebysexinteraction




26

effectsinvariance.Corticalthicknessshowedsignificantquadraticagebysexeffectsintworegions;

leftsuperiorfrontalcortexandrightlateralorbitofrontalcortex.

SexDifferencesinAnatomicalCorrelations

Finally,wetestedwhetherfemalesshowedgreaterdiversitythanmalesinanatomical

correlationsbycomparinginter-regionalanatomicalassociationsbetweenmalesandfemales.

Usingpermutationtesting(B=10000),thesignificanceofcorrelationdifferencesbetweenmales

andfemaleswasassessed.

Ofthe91subcortical-subcorticalcorrelationcoefficients,2%showedsignificantlystronger

correlationsinmales,while,unexpectedly,19%showedstrongercorrelationsinfemales(tested

two-sided)(Figure6A).Achi-squaretestofindependenceshowedthatthissignificantlydiffered

betweenmalesandfemales,X2(1,N=18)=10.889,p<.001.Forsurfacearea,nosignificant

differencebetweenmalesandfemaleswereobserved:significantlystrongermalehomogeneitywas

observedin4%ofthe2,278uniqueanatomicalcorrelations,andsimilarlyfemalesalsoshowed

significantlystrongercorrelationsin4%oftheanatomicalassociations(Figure6B).Forthickness,

strongermalethanfemalehomogeneitywasobservedin21%ofthecorrelations,whilestronger

femalecorrelationswereobservedin

27

greatermalebrainstructuralvarianceatbothupperandlowertailsofbrainmeasures(Wierengaet

al.2017).Thesevarianceeffectsseemtodescribeauniqueaspectofsexdifferencesinthebrain

thatdoesnotfollowtheregionalpatternofmeansexdifferences.Anovelfindingwasthatsex

differencesinvarianceappearstableacrossthelifespanforaround50%ofsubcorticalvolumes,

70%ofcorticalsurfaceareameasuresandalmostallcorticalthicknessmeasures.Unexpectedly,

regionswithsignificantchangeinvarianceeffectsacrosstheagerangeshoweddecreasingvariance

differencesbetweenthesexeswithincreasingage.Finally,weobservedgreatermaleinter-regional

homogeneityforcorticalthickness,butnotforsurfaceareaorsubcorticalvolumes,partly

replicatingpriorresultsofgreaterwithin-subjecthomogeneityinthemalebrain(Wierengaetal.

2017).Unexpectedly,subcorticalregionsshowedstrongerinterregionalcorrelationinfemalesthan

inmales.

Greatermalevariancewasmostpronouncedinbrainregionsinvolvedinplanning,regulation

andinhibitionofmotormovements(pallidum,rightinferiorparietalcortexandparacentral

region),episodicmemory(hippocampus),andmultimodalsensoryintegration(thalamus)(Aron,

Robbins,andPoldrack2004;Burgess,Maguire,andO'Keefe2002;Grillneretal.2005).Inaddition,

theearlypresenceofsexdifferencesinbrainstructuralvariabilitymaybeindicativeofgenetic

effects,inlinewithfindingsinapediatricsample(Wierengaetal.2017).Wealsoobservedthatsex

differencesinstructuralvariationareeitherstableormayreduceinoldage.Longitudinaldesigns

are,however,neededtoaddressthemechanismsunderlyingthisobservation.

Theexpressionofgreatermalevariabilityinbothupperandlowertailsofthedistributionmay

berelatedtoarchitecturalandgeometricconstraintsthatarecriticalforadelicatebalancefor

effectivelocal-globalcommunication.Forexample,neuronsonlypartlyregulatetheirsize,andthe

numberofneuralconnectionsdoesnotvarystronglywithneocorticalsizeacrossspecies(Stevens

1989).Althoughaxonsizeandmyelincancompensatefiringratesinlargerbrainsbyspeedingup




28

conductiontime,thereisalimitedenergybudgettooptimizebothvolumeandconductiontime

(Buzsáki,Logothetis,andSinger2013).Assuch,extremebrainstructure(inbothdirections)may

comeatacost.Thisisinlinewithrecentfindingsthatshowthatextremeneuralactivitypatterns

mayinducesuboptimalexpressionsofmentalstates(NorthoffandTumati2019).Interestingly,it

hasbeenfoundthatindividualswithautismspectrumdisordershowatypicalpatternsofbrain

structureanddevelopmentinboththeupperandlowerrange(Zabihietal.2019),suggestinga

possiblelinkbetweengreatermalevariabilityandvulnerabilityfordevelopmentaldisorders(see

alsoAlnæsetal.2019)).Togetherwithourfindings,thisopensupnewapproachesto

understandingsexbiaseddevelopmentaldisorders,beyondgroup-levelmeandifferences.

Althoughmostresultsshowedstablesexdifferenceswithincreasingage,halfofthesubcortical

regionsandaquarterofthecorticalsurfaceareameasuresshoweddecreasingsexdifferencesin

variance.Whatstandsoutisthatinalltheseregions,sexdifferencesinvariancewerelargestin

youngcomparedtoolderage.Thisisindicativeofearlymechanismsbeinginvolved.Furthermore,

forsubcorticalregions,thepatternsshowedlargervolumetricincreasesinfemalestheninmales.

Forsurfacearea,interactioneffectsshowedmostlystablevarianceacrossageinfemales,but

decreasesinvariabilityinmales.Theobservationthattherewerenosignificantquadratic

interactionsmakesitunlikelythatpubertalhormonesmayaffectgreatermalevariance.Yet,the

decreaseinmalevarianceinolderage,maybeindicativeofenvironmentaleffectslaterinlife.

Alternativeexplanationmaybethelargernumberofclinicalorevendeathratesinmalesthatmay

leadtosomesexdifferenceinsurvival(Chenetal.2008;Ryanetal.1997).

Factorsunderlyingorinfluencingsexdifferencesinthebrainmayincludesexchromosomes,

sexsteroids(bothperinatalorpubertal),andtheneuralembeddingofsocialinfluencesduringthe

lifespan(Dawson,Ashman,andCarver2000).Althoughwecouldnotdirectlytestthese

mechanisms,ourfindingsofgreatermalevariance,thataremostlystableacrossage,togetherwith




29

thegreatermaleinter-regionalhomogeneityforcorticalthicknessaremostinlinewiththesingle

X-chromosomeexpressioninmalescomparedtothemosaicpatternofX-inactivationinfemales

(Arnold2012).WhereasfemalebraintissueshowstwovariantsofX-linkedgenes,malesonlyshow

one.Thismechanismmayleadtoincreasedmalevulnerability,asisalsoseenforanumberofrare

X-linkedgeneticmutations(Chenetal.2008;Craig,Haworth,andPlomin2009;Johnson,Carothers,

andDeary2009;ReinholdandEngqvist2013;Ryanetal.1997).Noneoftheothersexeffects

mentionedabovepredictthesespecificinterandintra-individualsexdifferencesinbrainpatterns.

Futurestudiesare,however,neededtodirectlytestthesedifferentmechanisms.Furthermore,the

observationthatgreatermalehomogeneitywasonlyobservedincorticalthickness,butnotcortical

surfaceareaorsubcorticalvolumes,mayspeculativelyindicatethatX-chromosomerelatedgenetic

mechanismsmayhavethelargesteffectoncorticalthicknessmeasures.

Thispaperhasseveralstrengthsincludingitssamplesize,theagerangespanningninedecades,

theinclusionofdifferentstructuralmeasures(subcorticalvolumesandcorticalsurfaceareaand

thickness)andtheinvestigationofvarianceeffects.Thesepointsareimportant,asmostobserved

meansexdifferencesinthebrainaremodestinsize(JoelandFausto-Sterling2016).Wewereable

toanalyzedatafromafarlargersamplethanthoseincludedinrecentmeta-analysesofmeansex

differences(Marwhaetal.2017;Ruigroketal.2014;Tanetal.2016),andaverywideagerange

coveringchildhood,adolescence,adulthoodandsenescence.Theresultsofthisstudymayhave

importantimplicationsforstudiesonmeansexdifferencesinbrainstructure,asanalysesinsuch

studiestypicallyassumethatgroupvariancesareequal,whichthepresentstudyshowsmightnot

betenable.Thiscanbeparticularlyproblematicforstudieswithsmallsamplesizes(Rousseletetal.

2017).

Thecurrentstudyhassomelimitations.First,themulti-sitesamplewasheterogeneousand

specificsampleswererecruitedindifferentways,notalwaysrepresentativeoftheentire




30

population.Furthermore,althoughstructuralmeasuresmaybequitestableacrossdifferent

scanners,thelargenumberofsitesmayincreasethevarianceinobservedMRImeasures,butthis

wouldbeunlikelytobesystematicallybiasedwithrespecttoageorsex.Inaddition,variance

effectsmaychangeinnon-linearwaysacrosstheage-range.Thismaybeparticularlyapparentfor

surfaceareaandsubcorticalvolumemeasures,astheseshowedpronouncednon-linear

developmentalpatternsthroughchildhoodandadolescence(Tamnesetal.2017;Wierengaetal.

2018).Also,theimbalancednumberofsubjectsacrosstheagerangemayhavediminished

variabilityeffectsintheolderpartoftheagerange.Thepresentstudyhasacross-sectionaldesign.

Futurestudiesincludinglongitudinaldataarewarrantedtofurtherexplorethelifespandynamics

ofsexdifferencesinvariabilityinthebrain.Last,onecaveatmaybetheeffectofmovementondata

qualityandmorphometricmeasures.Asmaleshavebeenshowntomovemorethanfemalesinthe

scanner(Pardoe,KucharskyHiess,andKuzniecky2016),thismayhaveresultedinslightunder

estimationsofbrainvolumeandthicknessmeasuresformales(Reuteretal.2015).Although

qualitycontrolwasconductedateachsiteusingthestandardizedENIGMAcorticalandsubcortical

qualitycontrolprotocols(http://enigma.ini.usc.edu/protocols/imaging-protocols/),whichinvolve

acombinationofstatisticaloutlierdetectionandvisualqualitychecksandasimilarnumberof

malesandfemaleshadpartiallymissingdata(52.4%males),wecannotexcludethepossibility

thatin-scannersubjectmovementmayhaveaffectedtheresults.Nevertheless,wedonotthinkthis

canexplainourfindingofgreatermalevarianceinbrainmorphometrymeasures,asthiswasseen

atboththeupperandlowerendsofthedistributions.

ConclusionsThepresentstudyincludedalargelifespansampleandrobustlyconfirmedpreviousfindingsof

greatermalevarianceinbrainstructureinhumans.Wefoundgreatermalevarianceinallbrain

measures,includingsubcorticalvolumesandregionalcorticalsurfaceareaandthickness,atboth




31

theupperandthelowerendofthedistributions.Theresultshaveimportantimplicationsforthe

interpretationofstudieson(mean)sexdifferencesinbrainstructure.Furthermore,theresultsof

decreasingsexdifferencesinvarianceacrossageopensanewdirectionforresearchfocusingon

lifespanchangesinvariabilitywithinsexes.Ourfindingsofsexdifferencesinregionalbrain

structurebeingpresentalreadyinchildhoodmaysuggestearlygeneticorgene-environment

interactionmechanisms.Furtherinsightsintotheontogenyandcausesofvariabilitydifferencesin

thebrainmayprovidecluesforunderstandingmalebiasedneurodevelopmentaldisorders.




32

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FigurelegendsFigure1.Sexdifferencesinvolumetricmeasuresofsubcorticalvolumes(left),corticalsurfacearea

(center),andcorticalthickness(right).Shownareeffectsizes(Cohen'sd-value)ofFDRcorrected

meansexdifferences.Greatermeanvaluesformalesaredisplayedinblue,greatermeanvaluesfor

femalesaredisplayedinred.Darkercolorsindicatelargereffectsizes.

Figure2.Sexdifferencesinvarianceratioforsubcorticalvolumes(Left),corticalsurfacearea

(center),andcorticalthickness(right).Shownarelogtransformedvarianceratios,where

significantlargervarianceratioformalesthanfemalesisdisplayedinbluerangingfrom0to1.

Darkercolorsindicatealargervarianceratio.

Figure3.Jitteredmarginaldistributionscatterplots(A)aredisplayedtogetherwiththeirshift

function(B)forthetopthreevarianceratioeffectsofsubcorticalvolumes(top),corticalsurface

area(middle)andcorticalthickness(right).Thecentral,darkestlineoneachdistributionisthe

median,notethatmainsexeffectsareremoved.Theotherlinesmarkthedecilesofeach

distribution.Theshiftvaluesareincluded,whichrefertothenumberofunitsthatthemale(upper)

distributionwouldhavetobeshiftedtomatchthefemale(lower)distribution.Confidenceintervals

areincludedforeachoftheseshiftvalues.

Figure4.Regionswheresexdifferencesinvariabilityofbrainstructureinteractedwithage

displayedforsubcorticalvolumes(left),corticalsurfacearea(center),andcorticalthickness(right).

Figure5.Sexdifferencesinvariabilityinteractedwithagein50%ofthesubcorticalvolumes,30%

ofthesurfaceareameasures,andonlyonethicknessmeasure.Threerepresentativeresultsare

shown:rightthalamusvolume(topleft),surfaceareaoftherightparahippocampalgyrus(top

right)andthicknessoftheleftinsula(bottomcenter).Absoluteresidualvaluesaremodeledacross




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theagerange.Effectsshowedlargermalethanfemalevarianceintheyoungeragegroup,thiseffect

attenuatedwithincreasingage.

Figure6A-C.Strongeranatomicalcorrelationsformalesthanfemalesareindicatedinblue(larger

homogeneityinmalesthanfemales),whilestrongercorrelationsforfemalesaredisplayedinred

(largerhomogeneityinfemalesthanmales).Thebottomlefthalfshowsthesignificantvariance

ratio’sonly,usingtwosidedpermutationtesting.Resultsaredisplayedforsubcorticalvolumes(A),

surfacearea(B)andcorticalthickness(C).Corticalregionsareorderedbylobeandhemisphere

(leftfrontal,leftoccipital,leftparietal,lefttemporal,rightfrontal,rightoccipital,rightparietal,right

temporal).

SupplementalFigure1.Boxplotvisualizationofcomparisonofrighthippocampalvolume,and

parahippocampalsurfaceareaandthicknessbeforeandafteradjustment.Asagerangesdifferedfor

eachcohortadjustmentswereperformedintwosteps:initially,alinearmodelwasusedtoaccount

forcohortandnon-linearageeffects.Next,randomforestregressionmodellingwasusedto

additionallyaccountforfieldstrengthandFreeSurferversion.Intheleftpanel,volumeswerenot

adjusted,thisdisplaystherawdataforeachcohort.Intherightpanel,volumeswereadjusted.

SupplementalFigure2.Correlationbetweenvarianceratioandvectorofd-valuesforeachregion.

Resultsshowasignificantassociationforsubcorticalvolumes(left),butnosignificantrelationfor

regionalcorticalsurfacearea(middle),orthickness(right).

SupplementalFigure3A.Sexdifferencesinvariabilityinteractedwithagein50%ofthesubcortical

volumes.Absoluteresidualvaluesaremodeledacrosstheagerange.Effectsshowedlargermale

thanfemalevarianceintheyoungeragegroup,andageneraltrendofdecreasingsexdifferencesin

variancewithincreasingage.




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SupplementalFigure3B.Sexdifferencesinvariabilityinteractedwithagein30%ofcorticalsurface

areameasures.Absoluteresidualvaluesaremodeledacrosstheagerange.Effectsshowedlarger

malethanfemalevarianceintheyoungeragegroup,andageneraltrendofdecreasingsex

differencesinvariancewithincreasingage.




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AcknowledgementsADHDNF-Study:TheNeurofeedbackstudywaspartlyfundedbytheprojectD8oftheDeutsche

Forschungsgesellschaftcollaborativeresearchcenter636.Barcelona1.5T,Barcelona3T:The

MaratóTV3Foundation(#01/2010,#091710).Barcelona-SantPau:MiguelServetResearch

ContractCPII16/0020(SpanishGovernment,NationalInstituteofHealth,CarlosIII);theGeneralitat

deCatalunya(2017SGR01343).Betula-UmeaUniversity:KAWallenbergFoundationtoLN.BIG-

Nijmegen1.5T;BIG-Nijmegen3T:TheBIGdatabase,establishedinNijmegenin2007,isnowpart

ofCognomics,ajointinitiativebyresearchersoftheDondersCentreofcognitiveNeuroimaging,the

HumanGeneticsandCognitiveNeurosciencedepartmentsoftheRadbouduniversitymedical

centre,andtheMaxPlanckInstituteforPsycholinguistics.TheCognomicsInitiativeissupportedby

theparticipatingdepartmentsandcentresandbyexternalgrants,includinggrantsfromthe

BiobankingandBiomolecularResourcesResearchInfrastructure(Netherlands)(BBMRI-NL)and

theHersenstichtingNederland.Theauthorsalsoacknowledgegrantssupportingtheirworkfrom

theNetherlandsOrganizationforScientificResearch(NWO),i.e.theNWOBrain&Cognition

ExcellenceProgram(grant433-09-229),theViciInnovationProgram(grant016–130-669toBF)

and#91619115.AdditionalsupportisreceivedfromtheEuropeanCommunity'sSeventh

FrameworkProgramme(FP7/2007–2013)undergrantagreementsnº602805(Aggressotype),nº

603016(MATRICS),nº602450(IMAGEMEND),andnº278948(TACTICS),andfromtheEuropean

Community'sHorizon2020Programme(H2020/2014–2020)undergrantagreementsnº643051

(MiND)andnº667302(CoCA).BrainandDevelopmentResearchCenter,LeidenUniversity:

EuropeanResearchCouncil(ERC-2010-StG-263234toEAC);ResearchCouncilofNorway

(#223273,#288083,#230345);South-EasternNorwayRegionalHealthAuthority(#2017112,

#2019069).BRAINSCALE:NederlandseOrganisatievoorWetenschappelijkOnderzoek(NWO

51.02.061toH.H.,NWO51.02.062toD.B.,NWO-NIHCProgramsofexcellence433-09-220toH.H.,

NWO-MagW480-04-004toD.B.,andNWO/SPI56-464-14192toD.B.);FP7Ideas:European




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ResearchCouncil(ERC-230374toD.B.UniversiteitUtrecht(HighPotentialGranttoH.H.);KNAW

AcademyProfessorAward(PAH/6635).BRCATLAS:NationalInstituteforHealthResearch(NIHR)

BiomedicalResearchCentreatSouthLondonandMaudsleyNHSFoundationTrustandKing’s

CollegeLondon.CAMH:BBRF;CanadianInstitutesofHealthResearch;NaturalSciencesand

EngineeringResearchCouncil;NationalInstituteofMentalHealth;CAMHFoundation;Universityof

Toronto.CardiffUniversity:WearegratefultoallresearcherswithinCardiffUniversitywho

contributedtotheMBBrainspanel,andCardiffUniversityBrainResearchImagingCentre(CUBRIC)

andtheNationalCentreforMentalHealth(NCMH)fortheirsupport.CEG(London):UKMedical

ResearchCouncilGrantG03001896toJKuntsi;NIHRBiomedicalResearchCentreforMental

Health,NIHR/MRC(14/23/17);NIHRseniorinvestigatoraward(NF-SI-0616-10040).CIAM:

UniversityResearchCommittee,UniversityofCapeTown;NationalResearchFoundation;South

AfricanMedicalResearchCouncil.CODE–Berlin:Lundbeck;theGermanResearchFoundation(WA

1539/4-1,SCHN1205/3-1).ConzelmannStudy:DeutscheForschungsgemeinschaft(KFO125,TRR

58/A1andA5,SFB-TRR58/B01,B06andZ02,RE1632/5-1);EUH2020(#667302);German

ResearchFoundation(KFO125).ENIGMACore:NIAT32AG058507;NIH/NIMH5T32MH073526;

NIHgrantU54EB020403fromtheBigDatatoKnowledge(BD2K)Program;CorefundingNIHBig

DatatoKnowledge(BD2K)programunderconsortiumgrantU54EB020403;ENIGMAWorldAging

Center(R56AG058854;PIPMT);ENIGMASexDifferencesInitiative(R01MH116147;PIPMT);

ENIGMASuicidalThoughtsandBehaviorWorkingGroup(R01MH117601;PINJ).ENIGMA

Lifespan:NationalInstituteofMentalHealth(R01MH113619,R01MH116147,R01MH104284);

NationalInstituteforHealthResearch(NIHR)BiomedicalResearchCentreatSouthLondonand

MaudsleyNHSFoundationTrustandKing’sCollegeLondon;PsychiatryResearchTrust;2014

NARSADYoungInvestigatorAward.ENIGMA-HIV(NHIV;HIV-R01):NIHgrantMH085604.

ENIGMA-OCD(IDIBELL):FI17/00294(CarlosIIIHealthInstitute).PI16/00889;CPII16/00048

(CarlosIIIHealthInstitute).ENIGMA-OCD(LondonCohort/Mataix-Cols):WellcomeTrustanda




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pumppriminggrantfromtheSouthLondonandMaudsleyTrust,London,UK(Projectgrantno.

064846).ENIGMA-OCD(vandenHeuvel1.5T;vandenHeuvel3T):TheDutchOrganizationfor

ScientificResearch(NWO-ZonMw)VENIgrant916.86.036;NARSADYoungInvestigatorsAward;

NetherlandsBrainFoundationgrant2010(1)-50.ENIGMA-OCD-3T-CONTROLS:SouthAfrican

MedicalResearchCouncil(SAMRC);SouthAfricanNationalResearchFoundation(NRF).FIDMAG:

GeneralitatdeCatalunya(2017SGR01271);severalgrantsfundedbyInstitutodeSaludCarlosIII

co-fundedbytheEuropeanRegionalDevelopmentFund/EuropeanSocialFund“Investinginyour

future”:MiguelServetResearchContract(CPII16/00018toEP-C,CPII19/00009toJR)and

ResearchProjects(PI18/00810toEP-C,PI18/00877toRS,andPI19/00394toJR);AGAUR;

CIBERSAM.GSP:R01MH120080,K01MH099232,R00MH101367,R01MH119243;R01MH101486;

K24MH094614.WethankRandyBucknerforaccesstothisdataset.HomburgMultidiagnosisStudy

(HMS)-Gottingen,CLING:CLING/HMS:TheCliNGstudysamplewaspartiallysupportedbythe

DeutscheForschungsgemeinschaft(DFG)viatheClinicalResearchGroup241‘Genotype-phenotype

relationshipsandneurobiologyofthelongitudinalcourseofpsychosis’,TP2(PIGruber;

http://www.kfo241.de;grantnumberGR1950/5-1);datastorageserviceSDS@hdsupportedby

theMinistryofScience,ResearchandtheArtsBaden-Württemberg(MWK)andtheGerman

ResearchFoundation(DFG)throughgrantINST35/1314-1FUGGandINST35/1503-1FUGG.

HUBIN:SwedishResearchCouncil(2003-5485,2006-2992,2006-986,2008-2167,K2012-61X-

15078-09-3,521-2011-4622,521-2014-3487,2017-00949);regionalagreementonmedical

trainingandclinicalresearchbetweenStockholmCountyCouncilandtheKarolinskaInstitutet;

KnutandAliceWallenbergFoundation;HUBINproject.IDIBELL:CarlosIIIHealthInstitute

(PI13/01958,PI16/00889,CPII16/00048);FEDERfunds/EuropeanRegionalDevelopmentFund

(ERDF)-awaytobuildEurope-;theDepartmentofHealthoftheGeneralitatdeCatalunya(PERIS

SLT006/17/249);AGAUR(2017SGR1262).IMpACT-NL:TheNetherlandsOrganizationfor

ScientificResearch(NWO),i.e.theVeniInnovationProgram(grant016-196-115toMH)andthe




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ViciInnovationProgram(grant016–130-669toBF);U54EB020403totheENIGMAConsortium

fromtheBD2KInitiative,across-NIHpartnership,andbytheEuropeanCollegeof

Neuropsychopharmacology(ECNP)Network“ADHDAcrosstheLifespan”;TheDutchNational

ScienceAgendaNeurolabNLproject(grant400-17-602).Indiana1.5T;Indiana3T:NIHgrantsP30

AG010133,R01AG019771andR01CA129769;SiemensMedicalSolutions;themembersofthe

PartnershipforPediatricEpilepsyResearch,whichincludestheAmericanEpilepsySociety,the

EpilepsyFoundation,theEpilepsyTherapyProject,FightAgainstChildhoodEpilepsyandSeizures

(F.A.C.E.S.),andParentsAgainstChildhoodEpilepsy(P.A.C.E.);theGE/NFLHeadHealthChallengeI;

theIndianaStateDepartmentofHealthSpinalCordandBrainInjuryFundResearchGrantProgram;

aProjectDevelopmentTeamwithintheICTSINIH/NCRRGrantNumberRR025761.Instituteof

MentalHealth,Singapore:SingaporeBioimagingConsortium(RPC-009/06)andNMRCCSSSP

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